This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Smallpox is a life threatening disease caused by exposure to variola virus, a highly contagious pathogen that is considered a biological threat agent. In the event of an accidental or deliberate aerosol exposure of variola, there are currently no recommended drugs for postexposure prophylaxis and/or treatment for smallpox. Cidofovir is an antiviral drug that can be used to treat infection in the event of a biological attack. An inhaled cidofovir dry-powder formulation is being developed to be used in post-exposure prophylaxis and treatment of aerosol exposure to variola. Inhaled cidofovir has been shown in multiple mouse studies to be highly efficacious against various pox models, producing long-term activity and retention in the lung tissue compared to injectable administration. Intravenous administration of cidofovir, although efficacious, results in lower lung levels, severe kidney toxicity, and requires a health-care worker to implement treatment. Inhalable cidofovir, alternatively, results in high drug levels in the lung, bypasses the kidneys, and is self-administered. Initially, we will evaluate the inhalable version of cidofovir in a rabbit model of poxvirus infection. Rabbitpox is an ideal animal model for studying poxviruses;it causes a syndrome similar to smallpox in rabbits when the animals are experimentally infected with the virus by aerosol. This antiviral evaluation model will assess if cidofovir effectively inhibits infection in aerosol-exposed rabbits while not causing undue kidney damage or other unwanted adverse effects. Based upon the preliminary results from the rabbitpox studies, we will use an advanced nonhuman primate model of smallpox disease (aerosolized monkeypox in monkeys) to perform efficacy studies to demonstrate that delivery of the antiviral drug by inhalation in the nonhuman primate mirrors that in humans and that such concentrations are positively associated with primate survival when used as a postexposure therapeutic in this lethal model. Results of these studies will establish the relative safety and preclinical efficacy of reformulated cidofovir as a viable antiviral therapeutic against smallpox.